1. Field of the Invention
The invention relates to compositions comprising silicone elastomers and antiseptics in homogeneous distribution, to a process for the preparation thereof and to the use thereof in medical articles.
2. Description of Related Art
Medical articles made of plastics (e.g. catheters) are currently used in a large number of applications for diagnostic and therapeutic purposes. Central venous catheters are used for example in modern intensive care for invasive monitoring and treatment strategies such as continuous haemofiltration. Urinary tract catheters are an essential component of modern medical care and are indispensable, for example in the treatment of impairments of the flow of urine. Although modern medical articles have substantially improved the treatment of intensive-care patients, their application is associated with considerable risks. The frequent use of plastics articles such as, for example, catheters has led to a drastic increase in so-called polymer-associated infections. Polymer-associated infections are in general mainly caused by multiresistant nosocomial pathogens which adhere to an article's plastic surface and then colonize it (Urogenitale Infektionen, Ed. A. Hofstetter, Springer 1999, 241-64).
Catheter-associated infections currently represent an important cause of morbidity and mortality of intensive-care patients. Recent studies demonstrate that 70 to 90% of nosocomially acquired urinary tract infections are associated with an instrumentation (catheterization) of the urinary tract. A single catheterization of the urinary bladder is followed by bacteriuria for example in 0.5 to 28% of patients. The incidence of catheter-associated urinary tract infections moreover depends on the catheter time and the age, sex and condition (immunocompetence) of the patient (Urogenitale Infektionen, Ed. A. Hofstetter, Springer 1999, 241-64). However, the use of catheters not only involves a higher risk of infection for the patients, but also causes high follow-up therapy costs. Givens and Wenzel were able to show that nosocomial urinary tract infections increase the postoperative inpatient stay by an average of 2.4 days and cause corresponding additional costs (I Urol. 1980, 124: 646-48). Prevention of catheter-associated infections therefore has the highest priority in modem medicine for both medical and economic reasons.
Catheter-associated infections, possibly developing into sepsis, are, besides traumatic and thromboembolic complications, a serious problem on use of central venous catheters in intensive care.
Numerous studies have revealed that coagulase-negative staphylococci, the transient organism Staphylococcus aureus and various Candida species are the main causes of catheter-associated infections. During application of the catheter, these microorganisms, which are ubiquitously present on the skin, penetrate the physiological barrier of the skin and thus reach the subcutaneous region and eventually the bloodstream. Adhesion of the bacteria to the plastic surface is regarded as an essential step in the pathogenesis of foreign-body infections. Adhesion of the cutaneous organisms to the polymer surface is followed by the start of metabolically active proliferation of the bacteria with colonization of the polymer. This is associated with production of a biofilm through bacterial excretion of extracellular glycocalix. The biofilm assists adhesion of the pathogens and protects them from attack by certain cells of the immune system. In addition, the film forms a barrier which is impenetrable by many antibiotics. Extensive proliferation of the pathogenic organisms on the polymer surface may finally be followed by septic bacteriaemia. Therapy of such infections requires removal of the infected catheter because chemotherapy with antibiotics would require unphysiologically high doses.
The incidence of bacterially induced infections with central venous catheters averages about 5%. Overall, central venous catheters prove to be responsible for about 90% of all cases of sepsis in intensive care. The use of central venous catheters therefore not only involves a higher risk of infection for the patients, but also causes extremely high follow-up therapy costs (subsequent treatment, extended stays in the clinic).
The problems associated with urinary tract and central venous catheters can be solved only in part by prophylactic measures such as, for example, hygienic measures (handling of the catheters, training of the staff) or routine endoluminal antibiotic administrations.
A rational strategy for preventing polymer-associated infections consists of modifying the polymeric materials used. The aim of this modification must be to inhibit bacterial adhesion and the proliferation of already adherent bacteria, for causal prevention of foreign-body infections in this way. This can be achieved, for example, by incorporating a suitable antimicrobially active substance into the polymer matrix (e.g. antibiotics), provided that the incorporated active ingredient can also diffuse out of the polymer matrix in a controlled manner. An infection-resistant material ought therefore to have the following properties:
1) wide range of effects against the microorganisms relevant for infections associated with the appropriate catheter, especially coagulase-negative staphylococci such as Staphylococcus aureus for central venous catheters and enterococcal, Proteus, Klebsiella, Enterobacter species with urethral catheters;
2) sufficient duration of the antimicrobial effect, the requirement being for durations of action of longer than 30 days;
3) protection of the internal and external surfaces of the materials; and
4) polymer modification must not impair either the biocompatibility (thromogenicity, cytotoxicity) or the mechanical properties (tensile strength, modulus, hardness) of the material.
Methods for producing antimicrobially modified polymers for medical applications have already been disclosed.
EP-A 0 696 604 describes aliphatic thermoplastic polyurethane-ureas which are hydrophilic owing to the inclusion of urea groups but are unable to prevent bacterial adhesion and proliferation on the catheter surface. EP-A 1 067 974, EP-A 0 927 222, EP-A 1 128 724 and EP-A 1 128 723 describe antibacterially effective thermoplastic compounds into which the active ingredients are introduced in sufficiently fine and homogeneous distribution by high viscosity processing techniques. Comparative experiments have shown that the shear forces in the extruder are, however, insufficient to achieve the required distribution of the powdered active ingredients in the silicone solid-phase rubbers employed for producing catheter tubings.
Polymer materials for medical applications which have active ingredient-containing coatings are also mentioned in EP-A 328 421. Descriptions are given of processes for producing the antimicrobially active coatings and methods for application onto the surfaces of medical devices. The coatings consist of a polymer matrix, in particular of polyurethanes, silicones or biodegradable polymers, and of an antimicrobially active substance, preferably of a synergistic combination of a silver salt (silver sulphathiazine) with chlorhexidine or an antibiotic. This publication describes combinations of various polymers, inter alia, also silicones, with antibiotics. However, the difficulties of incorporating powdered active ingredients into silicone rubbers are not dealt with. The process according to the invention is not described in this publication.
European patent EP-A 0 688 564 describes active ingredient-containing silicone elastomers whose delivery rate can be controlled by the density of crosslinking. The special significance of the particle size of active ingredients in silicone elastomers and how this is achieved is not mentioned. In addition, additives which assist the release of active ingredients are described but are deliberately dispensed with in the present invention.
U.S. Pat. No. 4,230,686 (Schopflin et al) describes room temperature-crosslinking (RTV) silicone elastomers which comprise non-ionic lipophilic active ingredients. According to this publication (column 5, lines 57 to 59), such silicone elastomers are suitable as active ingredient carriers with slow release only for lipophilic non-ionic active ingredients. In addition, column 7, lines 51 to 60, describe the incorporation of the active ingredients as dry powders into the silicone elastomers. The particle size is said in this case to be chosen in such a way that as the solubility of the active ingredient in water increases the size of the incorporated particles (4 to 400 μm) must be larger.